Increasingly, new drug targets are identified by genetic techniques and expressed without knowledge of the biology of the protein target. Gaining a better understanding of the biology associated with these targets often involves using a probe compound that strongly affects the target's operation in an organism. Thus, discovering such probes is an important problem in drug discovery. Likewise, discovering and developing drugs for novel targets is a continuing and important challenge. One possible approach to these problems is high-throughput screening. However, searching through huge numbers of compounds with a very low hit rate makes this method expensive and can be a significant barrier. Fragment-based screening is an attractive alternative. However, the structural biology tools used for fragment screening are expensive and time consuming. We propose to develop enthalpy array technology for fragment screening to make fragment screening more efficient and inexpensive. Enthalpy arrays, which are arrays of nanocalorimeters, provide a binding assay that is label-free, does not require immobilization of proteins, and will work well with weakly binding fragments. We propose to develop enthalpy array technology for pre-screening fragments prior to more expensive structural biology screening, making the latter step more efficient. In addition, enthalpy arrays can be used to determine binding strength, specificity, and binding enthalpy for use in fragment elaboration, the step after fragment hits are established. The goal of this proposed research is to develop enthalpy arrays to make fragment screening more broadly applicable, more efficient, and thereby more accessible to individual researchers, including those in academia and smaller biotech companies. PUBLIC HEALTH RELEVANCE: The main approach today for finding small compounds for biology research and drug discovery involves screening through a huge number of compounds, in many cases in the hundreds of thousands to millions. Screening a smaller number of "fragment" elements that have higher hit rates is an attractive alternative, but the structural biology tools used for screening are expensive and time consuming. The goal of this proposed research is to develop a new array technology to make fragment screening more efficient, more broadly applicable, and more accessible to individual researchers, including those in academia and smaller biotech companies.